| First Author | Wyler SC | Year | 2015 |
| Journal | ACS Chem Neurosci | Volume | 6 |
| Issue | 7 | Pages | 1198-205 |
| PubMed ID | 25642596 | Mgi Jnum | J:237675 |
| Mgi Id | MGI:5816438 | Doi | 10.1021/cn500331z |
| Citation | Wyler SC, et al. (2015) Pet-1 Controls Tetrahydrobiopterin Pathway and Slc22a3 Transporter Genes in Serotonin Neurons. ACS Chem Neurosci 6(7):1198-205 |
| abstractText | Coordinated serotonin (5-HT) synthesis and reuptake depends on coexpression of Tph2, Aadc (Ddc), and Sert (Slc6a4) in brain 5-HT neurons. However, other gene products play critical roles in brain 5-HT synthesis and transport. For example, 5-HT synthesis depends on coexpression of genes encoding the enzymatic machinery necessary for the production and regeneration of tetrahydrobiopterin (BH4). In addition, the organic cation transporter 3 (Oct3, Slc22a3) functions as a low affinity, high capacity 5-HT reuptake protein in 5-HT neurons. The regulatory strategies controlling BH4 and Oct3 gene expression in 5-HT neurons have not been investigated. Our previous studies showed that Pet-1 is a critical transcription factor in a regulatory program that controls coexpression of Tph2, Aadc, and Sert in 5-HT neurons. Here, we investigate whether a common regulatory program determines global 5-HT synthesis and reuptake through coordinate transcriptional control. We show with comparative microarray profiling of flow sorted YFP(+) Pet-1(-/-) and wild type 5-HT neurons that Pet-1 regulates BH4 pathway genes, Gch1, Gchfr, and Qdpr. Thus, Pet-1 coordinates expression of all rate-limiting enzymatic (Tph2, Gch1) and post-translational regulatory (Gchfr) steps that determine the level of mammalian brain 5-HT synthesis. Moreover, Pet-1 globally controls acquisition of 5-HT reuptake in dorsal raphe 5-HT neurons by coordinating expression of Slc6a4 and Slc22a3. In situ hybridizations revealed that virtually all 5-HT neurons in the dorsal raphe depend on Pet-1 for Slc22a3 expression; similar results were obtained for Htr1a. Therefore, few if any 5-HT neurons in the dorsal raphe are resistant to loss of Pet-1 for their full neuron-type identity. |
